Early Prognostic Biomarkers of Non-Relapse Mortality in Allogeneic Mismatched Unrelated Hematopoietic Cell Transplantation

Introduction A major challenge in allogeneic hematopoietic cell transplantation (HCT) has been advancing outcomes for individuals lacking a fully matched donor who require a mismatched unrelated donor (MMUD) HCT. Recently, the 15-MMUD study demonstrated encouraging results for post-transplant cyclophosphamide (PT-Cy)-based prophylaxis in MMUD recipients (Shaw, Jimenez, JCO 2021). Our retrospective analysis confirmed improvement in MMUD survival with PT-Cy compared to historical anti-thymocyte globulin (ATG)/calcineurin-based regimens (Jimenez, Blood Adv 2022). Elevations of plasma biomarkers such as Stimulation-2 (ST2) have demonstrated increased risk of non-relapse mortality (NRM) and GVHD, however these have not been validated in the MMUD setting. Here, we carried out a pilot study to determine if biomarker analysis of ST2, Chemokine ligand-9 (CXCL-9), and Regenerating islet-derived 3-α (REG3α) at Day 14 (D14) and 30 (D30) can identify patients at higher risk for NRM after MMUD HCT. Methods Patients with banked samples and underwent MMUD HCT with either ATG or PT-Cy as GVHD prophylaxis at the University of Miami between 2016 - 2020 were included. Enzyme-linked immunosorbent assays for ST2, CXCL-9, and REG3α were performed in batches on cryopreserved plasma. Descriptive statistics of demographic variables were compared using chi-squared, Fisher's exact, or Wilcoxon rank sum tests. ST2 values were treated as continuous variables, and CXCL-9 was dichotomized due to frequent values below the lower limit of detection. Cumulative incidences of NRM were analyzed with relapse as a competing risk. Time-dependent receiver operating curves (ROC) were constructed and Area Under the ROC Curve (AUC) calculated. Youden's index was used to select optimum thresholds for each biomarker. Results We included 47 patients (ATG: 23; PT-Cy: 24). The PT-Cy group had more bone marrow graft representation (50% vs 22%, p = 0.04) and more donors mismatched at >1 HLA-locus (29% vs 0%, p